Matrix Regenerative Nanoparticles to Improve the Tumor Microenvironment in Non-Small-Cell Lung Cancers

摘要

Non-small cell lung cancer is a leading cause of mortality among cancer patients. Despite their promise, response rates to new immune-checkpoint inhibitors (PD-1/PD-L1, tyrosine kinase) are <20%, and has been attributed to the tumor microenvironment (TME) which favors immune evasion and pro-tumorigenic processes such as macrophage polarization wherein the Ml (pro-inflammatory) macrophages switch to an M2 (pro-tumorigenic) phenotype. The TME is also compromised by the chronic degradation of the alveolar elastic matrix by elastases and matrix metalloproteases (MMPs) to generate elastin peptides that stimulate macrophage polarization. Exogenous doxycycline (DOX), an MMP inhibitor, has also been shown to attenuate macrophage polarization and separately, to augment elastic regeneration by adult cells, which is naturally deficient, but has several side effects due to high dosing when systemically delivered. Targeted delivery of nanoparticles (NPs) can ensure localized, predictable, and sustained drug delivery in the TME. Previously, we showed that cationic amphiphile surface functionalization of polymer NPs imparted them pro-elastogenic and anti-proteolytic effects separate from the released drug3. In this work, we developed IL-4R-D0X-NPs that will inhibit macrophage polarization.